PROJECT SUMMARY Obesity is associated with an incidence of cardiometabolic abnormalities and an increased risk for cardiovascular disease (CVD) and type 2 diabetes. Improvements in the severity of these cardiometabolic readouts are associated with improved disease outcomes and reduced risk for CVD. Common approaches to treat obesity include lifestyle interventions such as diet and exercise. Exercise is also a key treatment option for heart failure patients and for tackling CVD risk factors associated with type 2 diabetes. Although exercise improves patient outcomes, long-term adherence to an exercise routine is difficult for many patients, regardless of health status. Diseases like heart failure and obesity are associated with disrupted skeletal muscle function and metabolism (the mechanisms of which are not yet fully understood) and patients may experience difficulty exercising. The benefits of regular exercise underscore the need for interventions that promote exercise tolerance. We have identified the Golgi-resident protein, Site-1 Protease (S1P), as a novel regulator of skeletal muscle metabolism and exercise endurance. S1P is required for the subsequent activation of several key transcription factors, including the sterol regulatory element-binding protein family and the ER stress regulator ATF6. While S1P is known to play important roles in regulating diverse pathways involved in lipid metabolism, autophagy, and ER stress signaling, to date, the role of S1P in skeletal muscle metabolism remains unknown. Our proposed studies will undertake the following Aims: (1) elucidate the function of S1P in skeletal muscle metabolism and function under healthy conditions in our skeletal muscle-specific S1P knockout mice and (2) define a function for S1P in obesity-associated skeletal muscle dysfunction and cardiometabolic abnormalities using a diet-induced obesity mouse model. The candidate already has a strong background in S1P biology and cellular stress pathways, this K01 award will provide her with the necessary training and expertise in intermediary metabolism, skeletal muscle function, and exercise physiology to successfully complete the proposed studies. Her proposed career development plan includes: (a) quarterly meetings with her Mentorship Committee (composed of experts in metabolic, cardiovascular, and exercise research) who have an excellent track record of mentoring junior faculty into successful independent investigators, (b) relevant coursework and seminars/conferences, and (c) one-on-one individual mentor meetings. These activities are crucial for the successful completion of the proposed studies and for achievement of the candidate's long-term goal of leading a successful independent lab that integrates her strong background in cellular stress pathways and S1P biology with the proposed Mentoring Goals to discover novel mechanisms in obesity-associated cardiovascular disease and skeletal muscle dysfunction. Future work in her lab will also focus on targeting mechanisms she uncovers to develop therapeutic interventions for metabolic disease.